When a bone-replacement material is implanted in patient, the formation of living bone may be induced at the surface of the bone. This is termed osteoconduction. In addition, living bone may in certain circumstances form within the material itself, penetrating the structure of the bone-replacement material. This is termed osteoinduction.
When osteoinduction occurs, bone is formed at a non-bony (i.e. ectopic) site. Osteoinduction is thought to be beneficial because, over time, the growth of bone penetrating a material can result in the more resilient integration of the bone-replacement material into already existing bone at, for example, the site of an osseous defect. However, many osteoconductive biomaterials do not exhibit osteoinduction.
Osteoinduction is promoted and/or accelerated by osteoinductive materials. In other words, osteoinductive materials are capable of inducing bone growth and the formation of bone in non-osseous tissue. When implanted in patients, osteoinductive materials are of significant therapeutic value because they promote and accelerate bone growth. For example in patients with compromised bone biology, the promotion and acceleration of bone repair can lead to shorter fracture-repair times and a lower incidence of non-unions or pseudo-arthroses.
To date, the most popular way of achieving osteoinduction in a biomaterial has been to include powerful cytokine proteins in a therapeutic form. The best known and most widely used of these proteins are the Bone Morphogenetic Proteins (BMP), particularly BMP-2 and BMP-7. These have been provided as recombinant human proteins (as present for example in the ‘InFuse’® and ‘OP-1’ bone replacement materials currently on the market), or as gels, powders or fibres derived from highly processed cadaver human bone and generically referred to as Demineralised Bone Matrix (DBM).
The disadvantages of using these proteins are well-known. While Bone Morphogenetic Protein products are certainly effective in their ability to promote rapid bone growth in preclinical studies, the use of recombinant human Bone Morphogenetic Protein products can also result in significant negative side-effects, such as uncontrolled bone resorption, runaway bone formation and, from a financial viewpoint, extremely high costs per therapeutic unit. Numerous clinical adverse events have been recorded using these highly-potent therapies, some resulting in major harm to patients. The mechanisms behind the occurrence of these adverse events are not currently well-understood.
In addition, the performance of products derived from Demineralised Bone Matrix is known to be highly variable and very donor-dependant. One solution to this would be to batch mix products from different donors. However, as all Demineralised Bone Matrix products have to maintain lot traceability, batch mixing is not possible. In addition, the levels of Bone Morphogenetic Proteins (from which the Demineralised Bone Matrix's osteoinductive properties are thought to derive) are very low and below established therapeutic thresholds for predictable, repeatable performance. As a result of these drawbacks, Demineralised Bone Matrix products have not demonstrated equivalent performance to current, commonly-used therapies in other equivalent orthopaedic and neurosurgical fields.
Another disadvantage of conventional Bone Morphogenetic Protein products is that they are not localised to a persistent scaffold which supports bone growth. Specifically, Bone Morphogenetic Protein products are typically provided as liquids which have to be adsorbed onto suboptimal scaffolds. The unpredictability of the absorption process can result in insufficient adsorption of the proteins, followed by implant compression and extrusion of the active agent into nerve spaces, causing severe harm or disability once bone formation has eventually been induced.
An alternative approach to relying on intentionally-introduced Bone Morphogenetic Proteins to provide osteoinductive activity is to provide a material having intrinsic osteoinductivity. The material is typically a scaffold material that itself promotes and accelerates bone growth without having to be treated with Bone Morphogenetic Proteins before being implanted into a patient.
One approach to provide an osteoinductive material has been to select a material that is resorbable. For example, the dissolution of calcium and phosphate from a calcium phosphate material are thought by some to be the key to providing an osteoinductive material. This approach is extended in, for example, PCT/NL2006/000210, which suggests that the dissolution of certain trace elements from a calcium phosphate material further promotes osteoinduction.
Another example of material that is claimed to have intrinsic osteoinductivity is described in U.S. Pat. No. 6,302,913. This material is “bioinert”, but, according to U.S. Pat. No. 6,302,913, has a surface geometry with a series of concavities that is said to concentrate Bone Morphogenetic Proteins absorbed from circulatory fluid in order to induce bone formation. However, these types of materials have also not yet resulted in strong in vivo promotion of bone growth.
As a result of at least some of the drawbacks with the prior art, the inventors of the present invention have set about to provide a material having intrinsic osteoinductivity but without relying on the sometimes unpredictable dissolution of trace elements or manipulation of surface geometry to provide osteoinduction.
EP 0951441 describes the synthesis of a dense osteoconductive silicon-substituted hydroxyapatite material.